Summary: Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain Chronic, life-disrupting pain, such as allodynia from chemotherapy induced peripheral neuropathy (CIPN), is difficult to manage. In this Phase I SBIR, Abalone Bio proposes to develop a first-in-class specific CB2 agonist antibody that is BOTH an effective and safe analgesic against CIPN as well as a co-therapy to enable opioid-based pain management without developing tolerance. CIPN occurs in >30% of chemotherapy patients treated with taxanes, and in various degrees for other therapies. Taxane CIPN is an untreated chronic condition that involves various degrees of allodynia, for which there is no demonstrated relief by any drug. Opioids, while frequently prescribed, are not clinically proven to effectively treat CIPN. On the contrary, heavy usage can lead to tolerance to opioids, and in turn opioid use disorders (OUDs). Efforts to develop drugs aimed at novel pain targets, including the peripheral cannabinoid receptor CB2, have so far yielded lackluster performance in clinical trials. Small-molecule CB2 agonists have been shown to reduce allodynia and reduce opioid tolerance in an established mouse model of chronic chemotherapy-induced peripheral neuropathy (CIPN). But small-molecule CB2 agonists have drawbacks: they are rapidly cleared, undesirably stimulate brain CB2 receptors, and cross-react with CB1 receptors in the periphery and in the brain. Abalone?s CB2 agonist antibody will be BOTH highly specific and thus will not cross-react with CB1 receptors in the periphery avoid CB2 receptors, and will also avoid the stimulation of brain CB2 receptors by being naturally restricted to peripheral tissues by the blood-brain barrier. By using our proprietary FAST platform, we isolated three single-chain camelid VHH domain antibodies hits (a.k.a. ?nanobodies?) consistent with agonist activity for human CB2. In this Phase I work, the first aim will be to identify in vitro at least 2 therapeutic-format VHH-Fcs with with Kd <2.5 nM for human CB2, Kd <25 nM for mouse CB2, and EC50 of AC inhibition or ERK activation <25 nM for human and mouse CB2. To do this, we?ll find suitable VHHs using FAST, convert them to FC fusions and produce protein for assays. We?ll measure hit function using mammalian cell-based assays and measure hit affinity (apparent KD) using flow cytometry on live cells. For antibody leads meeting criteria the second aim will be to assess in vivo effect on allodynia and opioid tolerance and identify at least 1 VHH-Fc that either or both reduces allodynia to ?80% of baseline levels and extends morphine efficacy at day 3 of morphine treatment to ?80% of day 1. We?ll use a broadly accepted C57BL/6J mouse model of CIPN and study their pharcokynetics, advancing all non-toxic leads to pharmacodynamic studies to determine dosing regime for subthreshold analgesia. Then we?ll measure prevention of opioid tolerance and CB2 specificity. The impact of this work could be very broad with our CB2 agonist antibody drug becoming a class-defining non-opioid analgesic and co-therapy that prevents the development of opioid tolerance.